[1]廖飞飞,杨文文,路爱梅,等.麝香通心滴丸调控HIF-1α/HO-1通路抑制铁死亡缓解心肌缺血再灌注损伤研究[J].陕西中医,2025,46(2):147-152,158.[doi:DOI:10.3969/j.issn.1000-7369.2025.02.001]
 LIAO Feifei,YANG Wenwen,LU Aimei,et al.Shexiang Tongxin dripping pills alleviate myocardial ischemia-reperfusion injury through inhibition of ferroptosis via regulation of the HIF-1α/HO-1 signaling pathway[J].,2025,46(2):147-152,158.[doi:DOI:10.3969/j.issn.1000-7369.2025.02.001]
点击复制

麝香通心滴丸调控HIF-1α/HO-1通路抑制铁死亡缓解心肌缺血再灌注损伤研究
分享到:

《陕西中医》[ISSN:1000-7369/CN:61-1281/TN]

卷:
46
期数:
2025年2期
页码:
147-152,158
栏目:
基础研究
出版日期:
2025-02-05

文章信息/Info

Title:
Shexiang Tongxin dripping pills alleviate myocardial ischemia-reperfusion injury through inhibition of ferroptosis via regulation of the HIF-1α/HO-1 signaling pathway
作者:
廖飞飞12杨文文3路爱梅14曲 华2王 洁2龙霖梓2付长庚2
(1.北京中医药大学研究生院,北京 100029; 2.中国中医科学院西苑医院,北京 100091; 3.陕西省中医医院心病科,陕西 西安 710003; 4.北京中医药大学东直门医院,北京 100007)
Author(s):
LIAO Feifei12YANG Wenwen3LU Aimei14QU Hua2WANG Jie 2LONG Linzi2FU Changgeng2
(1.Graduate School,Beijing University of Chinese Medicine,Beijing 100029,China; 2.Xiyuan Hospital,China Academy of Chinese Medical Sciences,Beijing 100091,China; 3.Department of Cardiology,Shaanxi Provincial Hospital of Traditional Chinese Medicine,Xi'an 710003,China; 4.Dongzhimen Hospital,Beijing University of Chinese Medicine,Beijing 100007,China)
关键词:
心肌缺血再灌注损伤 缺氧/复氧 麝香通心滴丸 铁死亡 HIF-1α/HO-1信号通路
Keywords:
Myocardial ischemia-reperfusion injury Hypoxia/reoxygenation Shexiang Tongxin dripping pills Ferroptosis HIF-1α/HO-1 signaling pathway
分类号:
R 542.22
DOI:
DOI:10.3969/j.issn.1000-7369.2025.02.001
文献标志码:
A
摘要:
目的:探究麝香通心滴丸(STDP)对心肌缺血再灌注损伤(MIRI)的保护作用及其潜在机制。方法:采用AnaeroPack方法构建H9c2细胞缺氧复氧损伤(H/R)模型以模拟MIRI。将细胞随机分为对照组、模型组和麝香通心滴丸组,分别在不含药或含药的培养液中培养24 h后收集细胞。采用细胞计数试剂盒法(CCK-8)检测细胞增殖与活性,酶联免疫吸附法(ELISA)测定细胞上清液乳酸脱氢酶(LDH)水平,荧光探针法检测活性氧(ROS)水平以评估细胞的氧化应激状态,透射电镜(TEM)观察线粒体超微结构变化,Western blot检测低氧诱导因子-1α(HIF-1α)、血红素加氧酶-1(HO-1)信号通路相关蛋白的表达水平。结果:麝香通心滴丸在H9c2心肌细胞中未表现出明显细胞毒性,同时在H/R条件下显著抑制了细胞损伤。麝香通心滴丸通过降低ROS生成和LDH释放,显著缓解了H/R诱导的氧化应激。TEM观察显示,与对照组相比,模型组的线粒体呈现明显的萎缩并伴随典型的铁死亡特征,而麝香通心滴丸组的线粒体形态显著改善,趋于正常。进一步通过Western blot检测发现,模型组HIF-1α和HO-1蛋白表达显著上调,而麝香通心滴丸组显著抑制了这些蛋白的过度表达(P<0.05)。结论:麝香通心滴丸可能通过抑制HIF-1α/HO-1信号通路介导的铁死亡,减轻心肌缺血再灌注损伤。
Abstract:
Objective:To investigate the protective effects of Shexiang Tongxin dripping pills(STDP)on myocardial ischemia-reperfusion injury(MIRI)and elucidate the underlying mechanisms.Methods:An H9c2 cell hypoxia-reoxygenation(H/R)injury model was established using the AnaeroPack method to simulate MIRI.Cells were randomly divided into control,model,and STDP groups and cultured in STDP-free or STDP-containing medium for 24 hours before being harvested.Cell proliferation and viability were assessed using the Cell Counting Kit-8(CCK-8)assay.Lactate dehydrogenase(LDH)levels in the cell supernatant were measured using enzyme-linked immunosorbent assay(ELISA).Reactive oxygen species(ROS)levels were evaluated using a fluorescence probe method to assess oxidative stress.Mitochondrial ultrastructural changes were observed by transmission electron microscopy(TEM).Protein expression levels of hypoxia-inducible factor-1α(HIF-1α)and heme oxygenase-1(HO-1)in the signaling pathway were analyzed by Western blot.Results:STDP-containing medium exhibited no significant cytotoxicity in H9c2 cardiomyocytes and effectively reduced H/R-induced cell injury.STDP alleviated oxidative stress by decreasing ROS generation and LDH release.TEM observations revealed that,compared with the control group,the model group showed significantly shrunken mitochondria with characteristic ferroptosis features,whereas mitochondrial morphology in the STDP group was markedly improved,resembling normal conditions.Furthermore,Western blot analysis demonstrated that the expression levels of HIF-1α and HO-1 proteins were significantly upregulatedin the model group,whereas STDP treatment significantly suppressed the excessive expression of these proteins(P<0.05).Conclusion:STDP may alleviate MIRI by inhibiting ferroptosis mediated via the HIF-1α/HO-1 signaling pathway.

参考文献/References:

[1] ZHAO D,LIU J,WANG M,et al.Epidemiology of cardiovascular disease in China:Current features and implications[J].Nat Rev Cardiol,2019,16(4):203-212.
[2] LI J Y,LIU S Q,YAO R Q,et al.A novel insight into the fate of cardiomyocytes in ischemia-reperfusion injury:From iron metabolism to ferroptosis[J].Front Cell Dev Biol,2021,9:799499.
[3] VALKO M,JOMOVA K,RHODES C J,et al.Redox- and non-redox-metal-induced formation of free radicals and their role in human disease[J].Arch Toxicol,2016,90(1):5-37.
[4] GAMMELLA E,RECALCATI S,CAIRO G.Dual role of ros as signal and stress agents:Iron tips the balance in favor of toxic effects[J].Oxid Med Cell Longev,2016,2016:8629024.
[5] WOFFORD J D,CHAKRABARTI M,LINDAHL P A.Mossbauer spectra of mouse hearts reveal age-dependent changes in mitochondrial and ferritin iron levels[J].J Biol Chem,2017,292(13):5546-5554.
[6] HUANG C H,CHANG C C,KUO C L,et al.Serum iron concentration,but not hemoglobin,correlates with TIMI risk score and 6-month left ventricular performance after primary angioplasty for acute myocardial infarction[J].PLoS One,2014,9(8):e104495.
[7] 王浩然,冯琴,张振刚,等.麝香通心滴丸联合常规治疗对心肌缺血再灌注损伤患者的临床疗效分析[J].实用临床医药杂志,2023,27(13):76-80.
[8] 刘杨,张静文,张鑫,等.麝香通心滴丸联合尼可地尔片治疗PCI术后心肌缺血再灌注损伤的临床观察[J].疑难病杂志,2023,22(6):572-577.
[9] 李蒙,刘用,张健真,等.麝香通心滴丸预处理对大鼠心肌缺血再灌注损伤的保护作用机制[J].中西医结合心脑血管病杂志,2024,22(2):250-253.
[10] 陶丹江.美托洛尔联合麝香通心滴丸对冠心病心绞痛的效果分析[J].当代临床医刊,2023,36(4):50-52.
[11] PATEL M,RAMAVATARAMD V.Non transferrin bound iron:Nature,manifestations and analytical approaches for estimation[J].Indian J Clin Biochem,2012,27(4):322-332.
[12] YAN Y,YUAN N,CHEN Y,et al.SKP alleviates the ferroptosis in diabetic kidney disease through suppression of HIF-1α/HO-1 pathway based on network pharmacology analysis and experimental validation[J].Chin Med,2024,19(1):31.
[13] FENG X,WANG S,SUN Z,et al.Ferroptosis enhanced diabetic renal tubular injury via HIF-1α/HO-1 pathway in db/db mice[J].Front Endocrinol(Lausanne),2021,12:626390.
[14] YAO M,WANG Z,JIANG L,et al.Oxytocin ameliorates high glucose- and ischemia/reperfusion-induced myocardial injury by suppressing pyroptosis via AMPK signaling pathway[J].Biomed Pharmacother,2022,153:113498.
[15] 国锦,高燕,赵渤年.中药复方血清药理学研究方法进展[J].中华中医药杂志,2017,32(4):1656-1658.
[16] 王伟,刘星雨,尚云龙,等.基于血清药物化学与网络药理学探究麝香通心滴丸治疗冠心病的机制[J].中成药,2020,42(10):2768-2777.
[17] WEN J,WANG D,CHENG L,et al.The optimization conditions of establishing an H9c2 cardiomyocyte hypoxia/reoxygenation injury model based on an AnaeroPack system[J].Cell Biol Int,2021,45(4):757-765.
[18] LI H,YANG W,SHANG Z,et al.Dehydrocorydaline attenuates myocardial ischemia-reperfusion injury via the FoXO signalling pathway:A multimodal study based on network pharmacology,molecular docking,and experimental study[J].J Ethnopharmacol,2024,337(1):118738.
[19] ROTH G A,MENSAH G A,JOHNSON C O,et al.Global burden of cardiovascular diseases and risk factors,1990-2019:Update from the GBD 2019 study[J].J Am Coll Cardiol,2021,77(15):1958-1959.
[20] FENG J,HAN L,LIU Y,et al.A bibliometric study related to the treatment of myocardial ischemia-reperfusion injury[J].J Cardiothorac Surg,2024,19(1):405-409.
[21] ZHANG M,LIU Q,MENG H,et al.Ischemia-reperfusion injury:Molecular mechanisms and therapeutic targets[J].Signal Transduct Target Ther,2024,9:12-17.
[22] CHEN Y,GUO X,ZENG Y,et al.Oxidative stress induces mitochondrial iron overload and ferroptotic cell death[J].Sci Rep,2023,13:15515.
[23] PELL V R,CHOUCHANI E T,FREZZA C,et al.Succinate metabolism:A new therapeutic target for myocardial reperfusion injury[J].Cardiovasc Res,2016,111:134-141.
[24] KAELIN W G,RATCLIFFE P J.Oxygen sensing by metazoans:The central role of the HIF hydroxylase pathway[J].Mol Cell,2008,30:393-402.
[25] WICKS E E,SEMENZA G L.Hypoxia-inducible factors:Cancer progression and clinical translation[J].J Clin Invest,2022,132:e159839.
[26] LU C,ZHANG Z,FAN Y,et al.Shikonin induces ferroptosis in osteosarcomas through the mitochondrial ROS-regulated HIF-1α/HO-1 axis[J].Phytomedicine,2024,135:156139.
[27] CAMASCHELLA C,NAI A,SILVESTRI L.Iron metabolism and iron disorders revisited in the hepcidin era[J].Haematologica,2020,105(2):260-272.
[28] WU Y,WANG J,ZHAO T,et al.Polystyrenenanoplastics lead to ferroptosis in the lungs[J].J Adv Res,2024,56:31-41.
[29] WU Y,WANG J,ZHAO T,et al.Di-(2-ethylhexyl)phthalate exposure leads to ferroptosis via the HIF-1α/HO-1 signaling pathway in mouse testes[J].J Hazard Mater,2022,426:127807.
[30] YANG W,WANG Y,FU C,et al.Quantitative visualization of myocardial ischemia-reperfusion-induced cardiac lesions via ferroptosis magnetic particle imaging[J].Theranostics,2024,14:1081.
[31] TANG W H,WU S,WONG T M,et al.Polyol pathway mediates iron-induced oxidative injury in ischemic-reperfused rat heart[J].Free Radic Biol Med,2008,45(5):602-610.
[32] CHANG C,REN Y,SU Q.Exploring the mechanism of Shexiang Tongxin dropping pill in the treatment of microvascular angina through network pharmacology and molecular docking[J].Ann Transl Med,2022,10(18):983.
[33] LU X,YAO J,LI C,et al.Shexiang Tongxin dropping pills promote macrophage polarization-induced angiogenesis against coronary microvascular dysfunction via PI3K/Akt/mTORC1 pathway[J].Front Pharmacol,2022,13:840521.
[34] 李蒙,李金根,刘佳,等.麝香通心滴丸改善冠状动脉慢血流的研究进展[J].世界中医药,2022,17(8):1180-1183.
[35] MIYAMOTO H D,IKEDA M,IDE T,et al.Iron overload via heme degradation in the endoplasmic reticulum triggers ferroptosis in myocardial ischemia-reperfusion injury[J].JACC Basic Transl Sci,2022,7:800-819.

相似文献/References:

[1]沈玉珏.黄芪多糖抑制缺氧/复氧损伤乳鼠心肌细胞凋亡与自噬机制研究[J].陕西中医,2021,(5):561.[doi:DOI:10.3969/j.issn.1000-7369.2020.05.004]
 SHEN Yujue.Mechanism of astragalus polysaccharides inhibiting cardiomyocyte apoptosis and autophagy in neonatal rats injured by hypoxia/reoxygenation[J].,2021,(2):561.[doi:DOI:10.3969/j.issn.1000-7369.2020.05.004]
[2]张 驰,李奥博,王心怡,等.温阳振衰颗粒调控miR-155/p38MAPK途径减轻大鼠心肌缺血再灌注损伤机制研究[J].陕西中医,2023,(8):1005.[doi:DOI:10.3969/j.issn.1000-7369.2023.08.003]
 ZHANG Chi,LI Aobo,WANG Xinyi,et al.Wenyang Zhenshuai granule reduce myocardial ischemia-reperfusion injury in rats via regulating miR-155/p38MAPK pathway[J].,2023,(2):1005.[doi:DOI:10.3969/j.issn.1000-7369.2023.08.003]
[3]张子洁,刘海健,彭 生.血必净对心肌细胞缺血再灌注损伤保护作用研究进展[J].陕西中医,2024,(1):139.[doi:DOI:10.3969/j.issn.1000-7369.2024.01.033]

备注/Memo

备注/Memo:
[基金项目]国家自然科学基金资助项目(82374413); 中国中医科学院科技创新工程(CI2021A05013)
更新日期/Last Update: 2025-02-08